Interleukin-8 (IL-8) is a member of the C—X—C chemokine family and acts as the primary chemoattractant for neutrophils. IL-8 is implicated in many inflammatory diseases. Although recruitment and activation of neutrophils are important in the normal inflammation response, excessive or continuous neutrophil recruitment often leads to acute inflammation (Matsumoto et al., J. Leukoc. Biol., 62 (5):581-7 (1997)). In addition, IL-8 is a potent angiogenic factor for endothelial cells and has been implicated in tumor angiogenesis.
Anti-IL-8 antibodies have been developed and used for treating bacterial pneumonia (U.S. Pat. No. 5,686,070), asthma (U.S. Pat. No. 5,874,080), and ulcerative colitis (U.S. Pat. No. 5,707,622). In addition, anti-IL-8 antibodies have been proposed for the treatment of Chronic Obstructive Pulmonary Disease (COPD), which is one of the most common chronic conditions and the fourth leading cause of death in the United States. COPD includes several related disorders that restrict the patient's ability to exhale. Accordingly, patients frequently experience dyspnea, or shortness of breath. Dyspnea typically causes patient discomfort, limits the patient's ability to engage in physical activity, and can induce further adverse health effects due to a diminished supply of oxygen. The two most common disorders associated with COPD are chronic bronchitis and emphysema, though patients suffering from COPD may also have chronic asthma, bronchiectasis, immunoglobulin deficiency, and cystic fibrosis.
Recently, it has been suggested that IL-8 may be a novel target for the treatment of diseases involving acute inflammation, such as gastrointestinal diseases (Ajuebor et al., Immunology, 105 (2):137-43 (2002)). IL-8 may also be a target for the treatment of cancer and tumors, such as melanoma (Singh et al., Histol. Histopathol, 15 (3):843-9 (2000) and systemic inflammatory syndrome (SIRS) (Dinarello et al., JAMA, 269 (14):1829-35 (1993)).
Other diseases associated with IL-8 include inflammatory diseases (Matsumoto et al., J. Leukoc. Biol., 62 (5):581-7 (1997)) such as ARDS, glomerlonephritis, alcoholic hepatitis, repurfusion injury, psoriasis (Jiang et al., Int J Dermatol, 40 (11):699-703 (2001)), rheumatoid arthritis (Kraan et al., J Invest Dermatol, 116 (2):319-29 (2001)), and inflammatory bowel disease (Imada et al., Scand J Gastroenterol, 36 (8):854-64 (2001)), pulmonary disorders, such as idiopathic pulmonary fibrosis (Lynch et al., Am Rev Respir Dis., 145 (6):1433-9 (1992)), tumor progression (Xie et al., Cytokine Growth Factor Rev., 12 (4):375-91 (2001)) and cancer and tumors generally, such as malignant melanoma, head and neck cancer, breast cancer, non-small cell lung cancer, ovarian cancer and brain cancer.
ABX-IL-8, a fully human monoclonal antibody generated with XenoMouse® technology, has been shown to block the activity of interleukin-8 (Press Release, Abgenix, Inc., Jan. 3, 2002). ABX-IL-8 has been shown to have potent anti-inflammation activity. ABX-IL-8 binds with high affinity to IL-8, blocks IL-8 binding to neutrophils, and inhibits neutrophil activation and migration (Yang et al., J. Leukoc. Biol., 66 (3):401-410 (1999)). Additional descriptions of human antibodies to IL-8 and methods of making them can be found in U.S. Pat. No. 6,150,584 (Kucherlapati et al.) and U.S. Pat. No. 6,713,610 (Kucherlapati et al.), incorporated by reference in their entireties.
High affinity antibodies to IL-8 can be desirable. However, it has been proposed that under physiological conditions, there is a ceiling on antibody affinity maturation in vivo for any antigen and that this ceiling is around 100 pM. (See generally, Foote, J. & Eisen, H. N., PNAS USA, 92:1254-6 (1995); Batista, F. D. & Neuberger, M. S., Immunity, 8:751-9 (1998); and Watts, C. & Davidson, H. W., EMBO J., 7:1937-45 (1998)). Moreover, even optimized antibodies, such as those that have been affinity matured in vitro by phage, yeast, or ribosome display, appear to have affinities that are limited to more than 10 pM. (See, “Demonstration of an in vivo generated sub-picomolar affinity fully human monoclonal antibody to interleukin-8,” Rathanaswami et al., Biochem. Biophys. Res. Commun. 334:1004-13 (2005), incorporated in its entirety by reference).